Cardiac pacemaker and uses thereof

ABSTRACT

The invention relates to improved cardiac pacemakers and methods of use thereof. In particular the cardiac pacemakers are useful for normalizing heart rates over resting heart rates in order to condition the heart to improve overall cardiac output.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/387,971, filed Sep. 25, 2014, which is a national stage filing underU.S.C. §371 of PCT International Application PCT/US2013/030752, filedMar. 13, 2013, which claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 61/616,162, entitled “CARDIAC PACEMAKERAND USES THEREOF,” filed on Mar. 27, 2012, which applications are hereinincorporated by reference in their entireties.

FIELD OF THE INVENTION

Improved cardiac pacemakers and methods of use thereof are described. Inparticular the cardiac pacemakers are useful for increasing heart ratesover resting heart rates in order to condition the heart and increasethe chamber size to improve overall cardiac output.

BACKGROUND OF INVENTION

It is known that individuals having a sedentary lifestyle, lacking inexercise, have more health problems than active individuals. One resultof a sedentary lifestyle is that the size of the heart's main chamberscan decrease. This is also occurs as an effect of prolonged hypertensionthat increases the muscle thickness at the cost of the chamber size. Adecrease in cardiac chamber volumes reduces the stroke volume which hasimplications on the generation of cardiac output by the heart. Thislimitation in cardiac output greatly reduces the ability to exercise.

Heart failure with preserved ejection fraction (HFpEF) is now the mostfrequent cause of heart failure. HFpEF is frequently associated withhypertension (HTN), concentric left ventricular hypertrophy (LVH), areduced LV chamber size and increased left ventricular stiffness.Impaired LV filling and small chamber size reduce the functionalcapacity through a limitation of cardiac output reserve. There is norational treatment for HFpEF.

SUMMARY OF THE INVENTION

Presented herein are devices and methods for improving heart functionusing cardiac pacemakers. In some aspects the invention is animplantable device. The implantable device is a cardiac pacemaker havinga sensor for detecting a heart rate, and a processor that is configuredto produce an output signal based on detection of a resting heart ratelevel, the output signal designed to elevate the heart rate over theresting heart rate level. The pacemaker optionally may include variousdetectors and functionalities. For instance the pacemaker may include amotion or physical activity detector, a position detector, a nightfunction, and/or a remote monitoring device.

The output signal of the device is produced when the resting heart rateis detected. In some embodiments the signal is produced with the restingheart rate is detected for at least 1, 5, 10, 15, or 30 minutes. Inother embodiments the resting heart rate is detected for at least onehour before the signal is produced.

The pacemaker in some embodiments comprises a housing, wherein thesensor extends from the housing. The sensor may have an input circuitthat receives a signal representative of a heartbeat sensed within aheart as a function of time.

In other aspects, the invention is a method for increasing a heart ratein a subject using a pacemaker when a resting state heart rate isdetected. In some embodiments the resting state heart rate is detectedfor at least 10 minutes or at least 30 minutes. In other embodiments thesubject is stimulated to have an increased heart rate for at least 30minutes.

In some embodiments the subject is not otherwise indicated for acurrently accepted treatment with a pacemaker. For instance, the subjectmay be an obese subject. Alternatively or additionally, the subject mayhave high blood pressure and/or heart failure with preserved ejectionfraction.

In other embodiments the pacemaker includes a motion or physicalactivity detector and wherein when the pacemaker detects movement orphysical activity of the subject, stimulation of the heart rate isreduced or pacing is discontinued.

Kits comprising one or more components of a pacemaker of the presentinvention are also provided. The kit may optionally include instructionsfor implanting and or operating the device of the present invention inhard copy or computer readable form.

Each of the limitations of the invention can encompass variousembodiments of the invention. It is, therefore, anticipated that each ofthe limitations of the invention involving any one element orcombinations of elements can be included in each aspect of theinvention. This invention is not limited in its application to thedetails of construction and the arrangement of components set forth inthe following description or illustrated in the drawings. The inventionis capable of other embodiments and of being practiced or of beingcarried out in various ways. Also, the phraseology and terminology usedherein is for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing”, “involving”, and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the invention are described in connection with the followingillustrative non-limiting drawings in which like numerals reference likeelements, and wherein:

FIG. 1 is a diagram of one embodiment of the inventive device shown inthe context of a heart. FIG. 1 depicts a cardiac pacemaker implanted ina body with a wire extending into the heart.

FIG. 2 is one embodiment of the cardiac pacemaker useful according tothe invention.

DETAILED DESCRIPTION

An increase in heart rate to above normal resting rates can enlarge theheart. In fact if this heart rate is well above normal rates patientscan develop enlarged heart chambers and a clinical phenotype that iscommonly called tachycardia induced cardiomyopathy. Endurance athletessuch as Tour de France bicycle riders can increase their chamber sizesto levels that are considered to be enlarged. This allows them toincrease cardiac output to exceptional levels that allows exercisecapacities at supra-physiological levels. Because these changes canregress with inactivity they are considered to be benign and are calledathlete's heart. Patients who develop atrial fibrillation withuncontrolled rapid ventricular conduction can develop a similarenlargement of their chamber volumes. If the heart rate is uncontrolledfor prolonged times it can result in “tachycardia inducedcardiomyopathy”. Restoration of the heart rate to normal levels with orwithout medications can quickly regress the enlargement of the mainchambers.

Myocardial tissue has plasticity and is capable of remodeling.Myocardium rapidly adapts to a change in circulatory demands. Forinstance, hypertension-induced LVH. Heart rate (HR) also affectsmyocardial remodeling. Increased HRs with endurance exercise and duringpregnancy contribute to an LV chamber enlargement of up to twice thenormal size. This type of LV remodeling is reversible.

LV chamber expansion without increase in LV mass can also be induced inanimals through tachycardia pacing. This phenotype also quickly reversesupon restoration of a normal heart rate. Tachycardia-induced LV chamberenlargement is also seen in patients after atrial fibrillationassociated ventricular tachycardia. In this setting it is not known ifrestoration of normal ventricular rates would be in of itself sufficientto reduce LV chamber size.

The invention in some aspects relates to myocardial pacing-induced LVremodeling. A symptomatic improvement of a patient with HFpEF afteratrial fibrillation with rapid ventricular conduction that restorednormal LV chamber dimensions and improved diastolic function has beenobserved. As described in the Examples section, a study designed toanalyze the feasibility of pacing-mediated LV remodeling in a porcinemodel. This proof-of-concept study includes control animals with anormal blood pressure (no HTN) and hypertensive LVH animals (HTN/LVH)induced by unilateral renal artery stenosis (2K1C model) to demonstratethat pacing-mediated LV remodeling can be accomplished in the typicalspectrum of normal EF phenotypes. The effect of low and moderate leveltachycardia on LV geometry and function will be studied longitudinallyto provide insights into the necessary HR requirements. The experimentaldesign will allow for within and between group comparisons. Beneficialeffects on diastolic function may be demonstrated in HTN/LVH animals ina 9 week survival study. This time is necessary to develop a phenotypeand study the effects of pacing-mediated LV remodeling.

In some aspects the invention involves the use of cardiac pacemakers tonormalize chamber volumes in patients with a reduction in heart size andlimitations in exercise capacity. Such patients are typicallysusceptible to heart failure symptoms such as shortness of breath.During resting times such as sleeping the pacemaker is programmed torates that will stimulate a chamber enlargement, in order to normalizeheart size. This approach would also mimic physiological aspects ofexercise and therefore condition the heart muscle.

Pacemakers can provide for heart rates observed in atrial fibrillation.According to the invention pacemakers can also provide the same effectin patients with small chamber volumes. The resulting increase inchamber size will allow them to exercise more and reduce symptoms.

Provided herein are methods and devices for performing normalizing heartchamber volumes in a subject. Heart chamber volumes are well known tothe skilled artisan. A subject having a small heart chamber volume isone that has a lower than normal cardiac output. Such a subject may bediagnosed as having a small heart chamber volume based onechocardiography or any other cardiac imaging modality, cardiac output,symptoms such as shortness of breath or other means known to the skilledphysician.

FIG. 1 illustrates one embodiment of the device in the context of aheart. A pacemaker 6 having a wire 4 extending therefrom is shown. Thewire 4 extends through the subclavian vein 12 and past the superior venacava 2 in the example. The wire optionally splits into a wire to theright atrium 10 and a wire to the right ventricle 8. The sensors orelectrodes typically detect electrical activity in the heart and senddata through the wires to the computer in the processor. If the heartrhythm is a resting heart rhythm, the computer will direct theprocessor/generator to send electrical pulses to the heart. The pulsesthen travel through the wires to reach heart, where the heart isstimulated to increase heart rate.

A cardiac pacemaker as used herein is a self-contained unit that sendselectrical stimulation to the heart. Typically a pacemaker is implantedinto a subject to alleviate symptoms of decreased cardiac output relatedto an abnormally low heart rate and/or rhythm. Pacemakers are generallyused for persistent, symptomatic second- or third-degreeatrioventricular (AV) block and symptomatic sinus and atrialbradycardia. While the methods of the invention may be accomplishedusing standard pacemakers known in the art, the methods are pacemaker isprogrammed to perform a different function—that is to increasestimulation of the heart at certain times. Pacemakers have beendescribed in for instance: US2001012954A, U.S. Pat. No. 4,688,573A, U.S.Pat. No. 4,803,987A, U.S. Pat. No. 5,467,773A, U.S. Pat. No. 3,885,552A,U.S. Pat. No. 5,694,940A, U.S. Pat. No. 6,485,416B, U.S. Pat. No.3,885,552A, U.S. Pat. No. 4,567,892A each of which is incorporated byreference.

A pacemaker may comprise a number of pacemaker components, such as ananalog commutator, area amplifier, peak amplitude amplifier, pulsewidth-hold control circuit, pacer pulse selector, pacer pulse amplifier,ecg amplifier, high speed electro-cardiogram ecg preamplifier, controllogic system, VCO audio system. Pacemakers have been described in forinstance: US2001012954A, U.S. Pat. No. 4,688,573A, U.S. Pat. No.4,803,987A, U.S. Pat. No. 5,467,773A, U.S. Pat. No. 3,885,552A, U.S.Pat. No. 5,694,940A, U.S. Pat. No. 6,485,416B, U.S. Pat. No. 3,885,552A,U.S. Pat. No. 4,567,892A each of which is incorporated by reference.

In some embodiments the pacemaker may be a single-chamber pacemaker, inthis type, only one pacing lead is placed into a chamber of the heart,either the atrium or the ventricle. In other embodiments the pacemakermay be a dual-chamber pacemaker. Here, wires are placed in two chambersof the heart. One lead paces the atrium and one paces the ventricle.This type more closely resembles the natural pacing of the heart byassisting the heart in coordinating the function between the atria andventricles. A cardiac pacemaker system typically consists of a battery,a computerized generator or processor, and wires with sensors sometimesreferred to as electrodes on one end. The battery and thegenerator/processor are located in the housing. The battery powers thegenerator/processor. The wires extend from the housing and connect thegenerator to the heart. An exemplary cardiac pacemaker is shown in FIG.2. A sensor in the form of a wire 24 extends from the housing 20. Thesensor will be implanted into a subjects heart. The sensor wire can besplit such that it interacts with multiple chambers of the heart, or itmay simply interact with one chamber. The sensor detects the heart rateand sends a signal to a processor in the pacemaker. Thus, the sensor mayhave an input circuit that receives a signal representative of aheartbeat sensed within a heart as a function of time. When a restingheart rate is detected on output signal is produced by a processor. Theoutput signal stimulates the heart to increase the heart rate over theresting heart rate level.

The subject may be stimulated to have an increased heart rate for anyamount of time. The amount of time that the heart rate is increased maybe predetermined. For instance the device may be set to produce anincrease in heart rate for at least 5, 10, 15, 30, or 60 minutes orlonger. Alternatively the device may include a motion or physicalactivity detector. Such a detector may be set to stop sending the signalfor increased heart rate upon motion or physical activity of thesubject. For instance if the subject gets up from rest the motion orphysical activity detector would sense movement by the subject and thepacemaker would stop sending the electrical signal that lead to anincreased heart activity. A pacemaker may also be programmed with both atime for the increased heart activity and a motion or physical activitydetector and the time or the motion of the subject, whichever happensfirst can signal the pacemaker to reduce the heart rate or shut off thesignal. Many pacemakers also had a motion detector that is typicallyused in subjects who cannot increase the heart rate with exercise. Inthese prior art devices, the motion detector increases the subjectsheart rate in response to activity to correct a pathological inabilityto increase the heart rate sufficiently with exercise. In contrast, tothe instant method as the subject starts to move to pacemaker “kicks in”and provides a high heart rate. This provides the subject with anincreased number of heart beats per minute which increases cardiacoutput and allows them to exercise again.

The pacemaker in some embodiments may be programmed to be responsive tothe position or movement of the body. For instance the pacemaker mayhave sensors that detect changes in the subject's physical activity andautomatically adjust the pacing rate to achieve a normal heart rate. Forexample, if the pacemaker is set to pace at a higher than resting heartrate at night while the subject is asleep, if the sensor detectsmovement suggesting the subject is awake and moving around the rate willbe reduced to a resting level. If the subject stops the movement for aperiod of time, such as 5 minutes then the pacemaker will be againprovide a rate that is higher than the resting rate.

A cardiac pacemaker may also comprise a control device including aposition detector connected to a movement sensor, wherein the positiondetector has a classification device for recognizing short movements.This type of sensor may also be used to detect motion or position thatwould trigger the pacemaker to operate at a resting rate.

The pacemaker may include a feedback sensor, such that when a low heartrate is detected the rate of the stimulation will be increased. Thepacemakers of the invention ideally have such a feature programmed intothe software.

The cardiac pacemakers useful according to the invention include anyknown commercially available cardiac pacemakers. The pacemakers areprogrammed or set to stimulate an increase in heart rate upon detectionof a resting heart rate or at a regular time of rest. Pacemakers includeboth temporary and permanent pacemakers, both of which are usefulaccording to the invention.

A pacemaker uses low-energy electrical pulses to stimulate the heart andchange the rate at which the heart beats. When the pacemaker is used inthe method of the invention it causes a slow heart rhythm, referred toas a resting heart rate to speed up. A resting heart rate as used hereinrefers to a heart rate that is within a range associated with a subjectat rest, such as a subject that is asleep. A normal resting heart rateis in the range from 40-90 per minute. The pacemakers described hereinare programmed to increase the heart rate to a level greater than anormal resting heart rate. In some embodiments the heart rate isincreased to a level with a normal range of an active subject. A normalrange of an active heart rate is 90-150/min. In some instances, it maybe desirable to raise the heart rate above normal levels. It issufficient according to the methods of the invention to continuouslypace the heart of subjects with small chamber volumes at increasedrates. In some embodiments it is desirable for the motion sensor to beintegrated into a feedback loop that controls pacing e.g. as the subjectis resting or sleeping and no motion is detected the pacemaker woulddeliver a higher pacing rate.

The pacemakers may also include other known functionalities such as aposition detector, a night function, and/or a remote monitoring device.Most contemporary pacemakers have a night function in which a heart ratecan be set at a fixed rate. Some pacemakers can also monitor bloodtemperature, breathing rate, and other factors and adjust your heartrate to these changes.

A night function feature in a pacemaker involves the control of the baserate using at least one sensor that can monitor a physiologicalparameter. Different phases such as rest phase and resumption ofactivity phase are detected by the sensor and send a signal to adapt thebase rate of the pacemaker accordingly. The base rate is allowed toincrease above the normally programmed resting rate or base rate inresponse to actual patient rest, to encourage a rapid cardiac rhythm tostimulate the heart muscle. Examples of night function mechanisms orsettings are disclosed in U.S. Pat. No. 5,645,576A, U.S. Pat. No.5,861,011A, and U.S. Pat. No. 6,975,903B. Cardiac electrical activityand pacemaker function may be monitored remotely in some instances. Forinstance medical personnel can remotely monitor the pacing and adjustthe pacing levels to increased levels when a patient is at rest.Examples of devices utilizing remote monitoring of vitals or feedbackinclude U.S. Pat. No. 5,919,141A, US2001056229A, US2001023360A,US2002143263A, US2002095093A, US2007282177A, US2006047205A,US2006211934A, US2007027371A, US2008269573A, US2011273309A, andUS2006074465A.

Another pacemaker feature is a rate adaptive pacemaker. These devicesinclude a mechanism for determining the demand of the patient, a pacingrate controlling element for controlling the pacing rate in response tothe patient's demand, and a pacing rate limiting mechanism forpreventing the pacing rate from becoming too low. Patents describingrespiration rate and pulmonary sensing and pacemaker feedback include:DE2346223A, U.S. Pat. No. 4,567,892A, U.S. Pat. No. 4,644,954A, U.S.Pat. No. 4,721,110A, U.S. Pat. No. 4,867,161A, EP0242510A, U.S. Pat. No.4,884,576A, U.S. Pat. No. 5,097,831A, U.S. Pat. No. 5,197,467A, U.S.Pat. No. 5,292,340A, U.S. Pat. No. 5,318,597A, U.S. Pat. No. 5,876,353A,U.S. Pat. No. 4,721,110A, U.S. Pat. No. 4,567,892A, and U.S. Pat. No.5,876,353A.

The methods of the invention are performed in a subject. A subject, asdiscussed herein, refers to a human or non-human vertebrate, but ispreferably a human. Preferably the human is a patient in need ofincreasing the cardiac output reserve. For instance, such a patient mayhave a smaller than normal heart volume. In some instances the subjectmay already be using a pacemaker or may have other disease indicationsthat call for the use of a pacemaker. In this case the pacemaker can beadditionally programmed to perform the methods of the invention.

In other embodiments the subject is not otherwise indicated for acurrently accepted treatment with a pacemaker. For instance, the subjectmay be an obese subject. Alternatively or additionally, the subject mayhave high blood pressure and/or heart failure with preserved ejectionfraction.

A subject typically in need of treatment with a pacemaker is a patientpredisposed to developing cardiac problems, such as for instance, asubject having one or more of the following characteristics: Decreasedvenous blood return, most commonly resulting from reduced blood volume(e.g., hemorrhage) or gravity causing blood to pool in the lower limbswhen standing upright; Ventricular diastolic failure (decreasedventricular compliance) caused, for example, by ventricular hypertrophyor impaired relaxation (lusitropy) or Inflow (mitral and tricuspid)valve stenosis, which reduces ventricular filling.

A subject in need of treatment with a pacemaker of the invention, mayalso include but is not limited to subjects with predispositions tocardiac problems, heart conditions associated with decreasing cardiacchamber sizes and associated heart dysfunction, decreased heart chambersize: Cardiomyopathy, high blood pressure, a subject having an injury orin circumstances where a patient's ability to exercise is impaired.Examples of factors associated with higher risk of cardiovasculardisease include but are not limited to HIV, Diabetes, Coronary arterydisease, high blood pressure, cardiomyopathy, atherosclerosis,disability, bedridden, air pollution, genetic history or family historyof heart failure, high levels of cholesterol, obesity, alcohol, cocaine,smoking or the use of other drugs toxic to the heart (treatment ofcancer), autoimmune diseases which have destroyed healthy body tissueand infections involving heart muscles.

Examples of biomarkers which may reflect a higher risk of cardiovasculardisease include but are not limited to coronary artery calcification,carotid intima-media thickness, carotid total plaque area, higherfibrinogen and PAI-1 blood concentrations, elevated homocysteine,elevated blood levels of asymmetric dimethylarginine, inflammation asmeasured by C-reactive protein, elevated blood levels of brainnatriuretic peptide (also known as B-type) (BNP).

Other configurations will be easily envisioned by the skilled artisanand are within the scope of the invention.

The present invention is further illustrated by the following Examples,which are not to be construed as limiting the scope of the invention inany manner.

EXAMPLES Example 1

The effect of low and moderate level tachycardia on LV geometry andfunction will be studied longitudinally to provide insights into thenecessary HR requirements. The experimental design will allow for withinand between group comparisons. Beneficial effects on diastolic functionmay be demonstrated in HTN/LVH animals in a 9 week survival study. Thisstudy will involve the development of a phenotype and the study of theeffects of pacing-mediated LV remodeling.

A total of 4 age-matched female Yucatan micro pigs (9 month) will bestudied in a 1×4 month longitudinal duplicate study.

One group will be animals with normal blood pressure (no HTN animals).These animals will be treated by the following protocol:

Day 1: Pacemaker implantation, sensing only to establish average heartrate

3 weeks: Baseline Echocardiogram, Blood Pressure

-   -   PPM: permanent A(V) pacing rate=1.5×average heart rate

5 weeks: Echocardiogram, Blood Pressure

-   -   PPM: permanent A(V) pacing rate=2×average heart rate

7 weeks: Echocardiogram, Blood Pressure

-   -   PPM off: sensing only

9 weeks: Echocardiogram, Blood Pressure, LV weight

Data processing and interim Analysis

A second group or treatment animals—hypertensive LVH animals (HTN/LVHanimals) will be treated as follows:

Day 1: Pacemaker implantation, sensing only to establish average heartrate

-   -   Unilateral renal artery stenosis (metal coil, fluoroscopic >80%        stenosis)    -   [MAP increase ˜30 mmHg, LV mass increase ˜20%]

3 weeks: Baseline Echocardiogram, Blood Pressure

-   -   PPM: permanent A(V) pacing rate=1.5×average heart rate

5 weeks: Echocardiogram, Blood Pressure

-   -   PPM: permanent A(V) pacing rate=2×average heart rate

7 weeks: Echocardiogram, Blood Pressure

-   -   PPM off: sensing only

9 weeks: Echocardiogram, Blood Pressure, LV weight

Data processing and final analysis

Echocardiogram: The animals will be sedated and intubated. Pacing willbe suspended and blood pressure will be assessed. A transthoracic andtransesophageal echocardiogram will be performed.

Parameters: Septal and posterior wall thickness, average LV wallthickness, end-diastolic and endsystolic LV diameter, modified Simpson'scalculation to evaluate LV end-diastolic and end-systolic volume(primary outcome), Devereux equation to estimate LV mass. Left atrialvolume will be assessed by the area-length method. Mitral inflow andlateral mitral annulus tissue Doppler to assess diastolic function. LVsystolic function (ejection fraction, stroke volume and cardiac output)will be calculated from LV volumes.

Each of the foregoing patents, patent applications and references ishereby incorporated by reference.

Having thus described several aspects of at least one embodiment of thisinvention, it is to be appreciated various alterations, modifications,and improvements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure, and are intended to be within the spirit and scope ofthe invention. Accordingly, the foregoing description and drawings areby way of example only.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, e.g., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, e.g., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements).

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (e.g. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements).

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

I claim:
 1. A cardiac pacemaker for implantation within a subject, thepacemaker comprising: a housing; at least one motion sensor configuredto detect movement of the subject and produce output indicative of themovement; and at least one processor in the housing, the at least oneprocessor being responsive to the output from the sensor and configuredto produce a pacing signal when the output from the at least one motionsensor indicates the subject is at rest, the pacing signal beingconfigured to increase a heart rate of the subject above a resting heartrate level, wherein the pacing signal is configured to stimulateremodeling of the subject's heart muscle.
 2. The cardiac pacemaker ofclaim 1, wherein the at least one processor is further configured tostop producing the pacing signal when the output from the at least onesensor indicates the subject is active.
 3. The cardiac pacemaker ofclaim 1, wherein the at least one processor determines that the subjectis at rest by detecting a lack of movement of the subject for a firstperiod of time.
 4. The cardiac pacemaker of claim 3, wherein the firstperiod of time is 5 minutes.
 5. The cardiac pacemaker of claim 1,further including an input circuit that receives a signal representativeof a heartbeat sensed within a heart as a function of time.
 6. Thecardiac pacemaker of claim 1, wherein the pacing signal is configured toincrease the heart rate of the subject to a heart rate between 90 beatsper minute and 150 beats per minute.
 7. The cardiac pacemaker of claim1, wherein the at least one processor is further configured to adjustthe pacing signal over time based on the output from the at least onemotion sensor.
 8. The cardiac pacemaker of claim 7, wherein adjustingthe pacing signal over time comprises: producing a first pacing signalconfigured to increase the heart rate of the subject to a first heartrate above the resting heart rate level; detecting output from the atleast one motion sensor that indicates the subject has remained at rest;and in response to said detecting, producing a second pacing signalconfigured to increase the heart rate of the subject to a second heartrate above the resting heart rate level, the second heart rate beinghigher than the first heart rate.
 9. The cardiac pacemaker of claim 1,wherein the output from the at least one motion sensor indicates thesubject is sleeping.